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Note that besides failing to show a benefit in the composite primary efficacy outcome, otamixaban did not show a benefit in any of the secondary efficacy outcomes, including procedural thrombotic complications.

Increased bleeding without a reduction in ischemic events spelled doom for otamixaban, a novel intravenous direct factor Xa inhibitor, during percutaneous coronary intervention (PCI), according to the randomized TAO trial.

Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) randomized to otamixaban had similar rates of the composite primary efficacy outcome of death or new myocardial infarction as patients treated with unfractionated heparin plus eptifibatide through day seven (5.5% versus 5.7%), according to Philippe Gabriel Steg, MD, of the Université Paris-Diderot, Sorbonne-Paris Cité in Paris, and colleagues.

In addition, those receiving otamixaban (0.140 mg/kg per hour) had significantly worse safety profiles, with more TIMI major or minor bleeding events through day 7 compared with the heparin arm (3.1% versus 1.5%), they reported in the study published online in the Journal of the American Medical Association.

The overall relative risk of bleeding was 2.13, and the risk remained twice as high regardless of the severity or bleeding classification scheme used:

TIMI major -- RR 2.32

Non-CABG-related major -- RR 2.35

CABG-related major -- RR 2.30

TIMI minor -- RR 1.90

The relative risk of intracerebral bleeds was 5.35, but with very wide confidence intervals (0.63-45.8).

Even in patients receiving a lower dose of otamixaban (0.100 mg/kg per hour), the rate of the primary outcome was not different and, in fact, showed a trend toward worse outcomes (RR 1.11, 95% CI 0.92-1.33). The data monitoring board stopped lower-dose arm of the trial for futility based on the interim analysis.

There is no longer any interest in developing this drug, Steg told MedPage Today during an interview.

Steg also presented the study at the European Society of Cardiology meeting in Amsterdam.

The phase 2 dose-ranging SEPIA-ACS 1 TIMI 42, which randomized more than 3,000 patients, showed a reduction in the combined outcome of death or myocardial infarction in patients treated with otamixaban and showed similar bleeding rates with otamixaban at midrange doses. This encouraged the investigators to conduct this phase 3 trial, which randomized 13,229 patients with NSTE-ACS and a planned early invasive strategy.

"A very important lesson here is that we cannot rely on the results of small studies that might not have enough power to determine whether a drug is ready for approval," Steg said.

Steg and colleagues noted the progress made in managing patients with NSTE-ACS undergoing PCI because of the availability of potent combinations of oral antiplatelet agents, injectable anticoagulants, and increasing use of an invasive strategy.

However, "there is no consensus on a single optimal injectable anticoagulant that can be used across the continuum of care from the emergency setting through revascularization (when applicable)," they wrote.

The median age was 62, less than a third of patients were women, and 87% were white. The median BMI was 27, slightly more than a quarter had diabetes, two-thirds had hypertension, and 19% had a previous heart attack.

Besides failing to show a benefit in the composite primary efficacy outcome, otamixaban did not reduce events in the separate components. Nor did the drug show a benefit in any of the secondary efficacy outcomes, including procedural thrombotic complications.

Also, an analysis of the primary outcome by 30 days confirmed the absence of a reduction with otamixaban.

"These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention," the authors concluded.

The authors noted two limitations of the study. First, 63% of patients had received injectable anticoagulation before randomization. Second, the duration of the study drug infusion was relatively brief.

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